All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Interactions between the commensal microflora and the gut immune system are critical for establishing a proper balance between immune host defense mechanisms and tissue health. Changes in gut bacteria composition described as “disbiosis” have been associated with intestinal inflammation and metabolic syndrome. The vast majority of studies on the interaction between commensal microbiota and the host have focused on gut bacteria, and the terms “intestinal microbiota” and “intestinal bacteria” are often used interchangeably. However, recent studies have begun to note that a fraction of mucosa-associated microorganisms are not bacterial. For example, commensal viruses can trigger gut inflammation by targeting host Paneth cells or indirectly by targeting commensal bacteria. Although a few studies have suggested the presence of commensal fungi in the gut, it is unknown whether they interact with the mucosal immune system or influence disease. As illustrated recently by Segmented Filamentous Bacteria (SFB) and Clostridium sp., even organisms representing a proportionally small fraction of the total microbiome can have profound effects on the host immune system. Thus it is important to evaluate whether gut fungi significantly influence the maintenance of host intestinal homeostasis.
Fungi are recognized by a number of immune receptors among which Dectin-1 has emerged as key for recognition, phagocytosis, and killing by myeloid phagocytes. Dectin-1 is a C-type lectin receptor that recognizes β-1,3-glucans found in the cell walls of nearly all fungi. Dectin-1 activates intracellular signals through CARD9 leading to inflammatory cytokine production and enhanced induction of Th17 immune responses. Deficiencies in either Dectin-1 or CARD9 result in enhanced susceptibility to pathogenic fungal infections in humans and mice. Polymorphic variants in the gene for CARD9 are strongly associated with Crohn's disease and ulcerative colitis in humans. Furthermore, anti-Saccharomyces cerevisiae antibodies (ASCA) against yeast mannan have been strongly associated with Crohn's disease. Together, these later findings suggest a possible link between immune responses to commensal fungi and intestinal disease.